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• Molecular_risk_stratification_in_patients_with_T1_colorectal_cancer_WES

  The introduction of bowel cancer screening has led to a significant increase in the proportion of patients being diagnosed with asymptomatic, early-stage colorectal cancer (CRC). Although the majority of these patients are successfully treated with surgery alone, a small proportion of patients have ‘born-to-be-bad’ aggressive lesions with early dissemination leading to distant metastases. Current standard of care histological assessment is unable to distinguish between these aggressive versus non-aggressive early lesions which is essential to provide appropriate clinical management decisions. This study aims to carry out molecular and histological profiling of approximately 300 T1 CRCs in order to develop a molecular stratifier based on the risk of relapse in early-invasive CRC. This novel T1 cohort will represent the world’s largest molecularly characterised T1 cohort of samples, with digital pathology assessment alongside whole exome sequencing, copy number variation analysis and 3’ RNA-seq. This data will be used to generate a robust panel of molecular and/or histological markers applicable to formalin-fixed paraffin embedded (FFPE) archival tissue which discriminates between T1 lesions based on risk of relapse, which will ultimately be used to inform clinical management of CRC at the earliest stages of the disease.

  Study EGAS00001005734

• Epigenome-wide methylation analysis of colorectal carcinoma, adenoma and normal tissue reveals novel biomarkers addressing unmet clinical needs

  Studies about CRC biomarker discovery have focused on methylation patterns in normal and colorectal tumor tissue, leading to a lack of knowledge of methylation in adenomas. Therefore, we performed the first epigenome-wide study to compare the epigenomes of all three tissue types combined, and to identify discriminatory biomarkers. Public Illumina MethylEPIC® data was collected from 552 normal, 118 carcinoma and 116 adenoma samples. Pairwise analyses were performed for discovery of differentially methylated probes (DMPs). We identified 693 813, 620 643 and 558 897 DMPs when comparing normal vs carcinoma, normal vs adenoma and adenoma vs carcinoma respectively. To double evidence (DE) these DMPs, analysis of Illumina 450K data from public datasets was performed. Through this analysis, 13 DE DMPs with │Δβ│≥0.3 were identified for adenoma vs carcinoma. A binary logistic regression model was generated to evaluate the discriminatory potential of these DE DMPS. The model was validated in an in-house experimental methylation dataset of 13 adenoma and 9 carcinoma samples. Our classifier reached a cross-validated AUC of 0.996 and 0.855 in the discovery and validation datasets respectively. A sensitivity and specificity of 96% and 95% were reached, with an overall accuracy of 96%. Our analysis show that methylation biomarkers have the potential to discriminate between normal, precursor and carcinoma tissues of the colorectum. More importantly, we highlight the power of the methylome, showing that DMPs can be used as biomarkers in the clinic to identify colorectal adenoma and carcinoma. 

  Study EGAS00001007017

• Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome

  The transgenerational maternal effects of PCOS in female progeny have been revealed. As there are evidence that a male equivalent of PCOS may exist, we asked whether sons born to mother with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a Swedish nationwide register-based cohort and a clinical case-control study from Chile we found that PCOS-sons are more often obese and dyslipidemic. Their serum miRNAs are found to potentially regulate PCOS-risk genes. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in F1 male offspring are passed down to F3. Small non-coding RNAs (sncRNAs) sequencing of F1-F3 sperm revealed distinct differentially expressed (DE) sncRNAs across generations in the androgenized, obese, and obese and androgenized lineages, respectively. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism. These findings strengthen the translational relevance highlighting a previously underappreciated risk of reproductive and metabolic dysfunction via the male germline transmission and potential molecular markers to study in future generations.

  Study EGAS00001007079

• Rifaximin stimulates nitrogen detoxification by PXR-independent mechanisms in human small intestinal organoids

  To study the effects of rifaximin on human small intestinal (hSI) organoids, we performed RNAseq in PXR knockdown hSI compared to control hSI.

  Study EGAS00001006857

• Single-cell spatiotranscriptomic dissection of ex vivo human heart right atrial appendage and pericardial fluid in ischemic heart disease and heart failure

  We use cardiac and pericardial fluid biopsies collected during open-heart surgery in control, ischemic heart disease, heart failure, and myocardial infarction context. For each sample, single-nuclei RNA sequencing experiment is performed. We also perform spatial transcriptomics on the heart samples. We annotate the cells in major cell types, in addition to subtypes annotation of vascular and immune cells. The disease annotation enables us to reveal substantial differences in gene expression at the cell subpopulation levels. Our results demonstrate the importance of high-resolution cellular type/state mapping in the elucidation of human cardiovascular disease pathogenesis.

  Study EGAS50000000653

• Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

  Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identified five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reasoned that their strong selection should prioritise them as key biomarkers for targeted therapies. We used primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number was associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC was statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway was independently observed in squamous lung cancer and triple negative breast cancer. These results suggest that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

  Study EGAS00001006200

• Low Density Genotyping from the Fragile Families and Child Wellbeing Study

  The Fragile Families and Child Wellbeing Study (FFCWS) is based on a stratified, multistage sample of 4898 children born in large U.S. cities (population over 200,000) between 1998 and 2000, where births to unmarried mothers were oversampled by a ratio of 3 to 1. This sampling strategy resulted in the inclusion of a large number of Black, Hispanic, and low-income families. The project “Low Density Genotyping from the Fragile Families & Child Wellbeing Study” uses saliva collected from a subset of FFCWS children at Year 9 and from teens at Year 15 to examine genetic variation using a genome-wide assay (Illumina PsychChip). In addition to the genotype data, a limited set of self reported and anthropomorphic measures are included.

  Study phs002417

• Origin of second malignancies in children

  Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely rare. We present four such clinical cases and through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary AML. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least in one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.

  Study EGAS50000000167

• Genome-Wide Association Study in Systemic Sclerosis

  The Scleroderma Family Registry and DNA Repository (Registry) was initially developed as a registry and bio-specimen repository of patients with systemic sclerosis (scleroderma), family members and unaffected healthy controls. A case-control design was later adopted due to the lack of availability of many parents in this adult-onset disease, which precluded a linkage approach. In addition to collecting demographic data, the registry included the collection of disease-pertinent, cross-sectional, clinical information from medical records of affected participants. Registry participants were >/= 18 years of age at enrollment. On the basis of medical record review, all cases were verified by the principal investigator to meet the eligibility criteria. 800+ blood samples from verified affected cases of European ancestry were selected for a Genome Wide Association Study (GWAS). These genetic data, as well as phenotypic data, are available in dbGaP. DNA, serum and plasma from Registry participants, which are currently being stored in the University of Texas Health Science Center - Houston, Scleroderma Registry Genetic Repository, are available for research purposes. However, not all of the 800+ registry participants who submitted a blood sample currently have DNA available due to depletion of some samples. In addition to including SNP data from the genome-wide (first study release) and immunochip (second study release) scan on the 800+ samples, the dbGaP database provides a set of data tables with phenotypic information collected from the participants in the registry.

  Study phs000357

• Defining the metastasome in colorectal cancer: Implications for hypotheses on metastasis evolution and personalized therapy (HIPO-032)

  Personalized cancer therapy aims at individual genetic changes characterizing primary cancers. Still, however, metastasis is the major clinically unmet problem, also due to an incomplete understanding of its molecular evolution.This study is the first to define the metastasis-specific whole genome landscape of human colorectal primary vs. matched metastatic lesions.Protein coding, ncRNA genes and 3’UTRs harbored about a third each of single nucleotide variations (SNVs)/indels, 19% of them being metastasis-specific. We found novel mutational hills among ncRNAs and 3’UTRs, copy number changes able to explain changes in microRNA expression in metastases, and novel metastasis-specific mutations in the 3’UTRs on important cancer signalling genes. Some metastatic lesions showed targetable mutations not detected in the primaries. Analysis of mutual exclusivity patterns supported a model that has progressive alterations in important colorectal cancer genes and revealed new partners. Metastatic lesions were enriched in SNVs, specific structural variations, and alterations in genes affecting cell adhesion and extracellular matrix interaction.Furthermore, a hepatic stellate activation cascade was enriched in metastases, suggesting genetic programs for site-specific colonization. Allele frequency distribution and mutational signature analysis suggests a common ancestor clone to both the primary tumor and the metastasis, with additional mutagenesis ongoing in both sites independently. Taken together, our results significantly add to hypothesis generation on metastasis evolution, and suggest novel metastasis-specific genomic changes which would be missed by current personalized therapy concepts. (HIPO-032)

  Study EGAS00001002717